Sonic hedgehog-associated medulloblastoma arising from the cochlear nuclei of the brainstem
Sonic hedgehog-associated medulloblastoma arising from the cochlear nuclei of the brainstem
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DOI：
10.1007/s00401-012-0961-0
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发表时间：
2012-04-01
影响因子：
12.7
通讯作者：
Schueller, Ulrich
中科院分区：
文献类型：
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作者：
Grammel, Daniel;Warmuth-Metz, Monika;Schueller, Ulrich
髓母细胞瘤是一种儿童恶性脑肿瘤，至少包括四个不同的分子亚群。我们以前曾描述过，小脑颗粒神经元前体可能会产生一个亚组的Sonic hedgehog（Shh）信号分子指纹。其他最近的数据表明，在背侧脑干的前体细胞可能作为Wnt相关髓母细胞瘤的细胞起源。为了了解Shh相关的髓母细胞瘤是否也能够在背侧脑干中发展，我们分析了两种转基因小鼠，分别在hGFAP和Math1阳性脑干前体群体中具有组成性Shh信号传导。我们的研究结果表明，在这两条线，髓母细胞瘤产生的颗粒神经元前体的耳蜗核，一个衍生物的听觉下菱形唇。该区域与小脑前下菱形唇的衍生物不同，其中成神经管细胞瘤在具有组成性活性Wnt信号传导的小鼠中出现。就其组织学和适当标记物的表达而言，来自小鼠耳蜗核的Shh肿瘤与人类Shh相关的髓母细胞瘤完全相似。此外，我们发现，在一系列的63人促结缔组织增生性髓母细胞瘤，21（33%）有一个非常密切的接触，耳蜗核的磁共振成像。总之，我们表明，前体的小鼠菱形唇，无论是发展成小脑或耳蜗颗粒神经元，可能会引起SHH相关的髓母细胞瘤，这对人类髓母细胞瘤的细胞起源具有重要意义。
Medulloblastoma is a malignant brain tumor of childhood that comprises at least four molecularly distinct subgroups. We have previously described that cerebellar granule neuron precursors may give rise to the subgroup with a molecular fingerprint of Sonic hedgehog (Shh) signaling. Other recent data indicate that precursor cells within the dorsal brain stem may serve as cellular origins for Wnt-associated medulloblastomas. To see whether Shh-associated medulloblastomas are also able to develop in the dorsal brainstem, we analyzed two lines of transgenic mice with constitutive Shh signaling in hGFAP- and Math1-positive brainstem precursor populations, respectively. Our results show that in both of these lines, medulloblastomas arise from granule neuron precursors of the cochlear nuclei, a derivative of the auditory lower rhombic lip. This region is distinct from derivatives of precerebellar lower rhombic lip where medulloblastomas arise in mice with constitutive-active Wnt signaling. With respect to their histology and the expression of appropriate markers, Shh tumors from the murine cochlear nuclei perfectly resemble human Shh-associated medulloblastomas. Moreover, we find that in a series of 63 human desmoplastic medulloblastomas, 21 (33%) have a very close contact to the cochlear nuclei on MR imaging. In conclusion, we demonstrate that precursors of the murine rhombic lip, which either develop into cerebellar or into cochlear granule neurons, may give rise to Shh-associated medulloblastoma, and this has important implications for the cellular origin of human medulloblastomas.